cAMP signaling in melanoma pathogenesis: Evidence for multiple microdomains playi

黑色素瘤发病机制中的 cAMP 信号传导：多个微域发挥作用的证据

• 批准号: 8685192
• 负责人: Jonathan Hale Zippin
• 金额: $ 17.12万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685192
• 关键词: Adenylate Cyclase; Basic Science; Benign; Beta Cell; Bicarbonate Ion; Bicarbonate Ions; Binding Proteins; Biological; Biology; Biopsy; CREB1 gene; Calcium; Cell Line; Cell Nucleus; Cell membrane; Cells; Cessation of life; Chemicals; Chemotaxis; Clinical Trials; Collaborations; Contact Inhibition; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Dermatology; Development; Diagnosis; Education; Forskolin; Funding; GTP-Binding Proteins; Genes; Genetic; Genome; Glucose; Goals; Golgi Apparatus; Growth; Growth Cones; Human; In Vitro; Institution; Intervention; Investigation; Journals; Knowledge; Lead; Lesion; Malignant Neoplasms; Mammalian Cell; Manuscripts; Medical; Medical center; Melanoma Cell; Memorial Sloan-Kettering Cancer Center; Mentors; Methods; Mitochondria; Modeling; Mus; NIH 3T3 Cells; Neoplasm Metastasis; Nerve Growth Factors; Neurons; Nevus; Nuclear; Oncogenes; PC12 Cells; PI3K/AKT; Pathogenesis; Pathway interactions; Physicians; Play; Protein Isoforms; Proteins; Publications; Ras/Raf; Reagent; Relative (related person); Reporting; Research; Research Personnel; Resources; Role; Scientist; Secure; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Source; Techniques; Training; Work; analog; anticancer research; base; calcium bicarbonate; effective therapy; genetic inhibitor; improved; inhibitor/antagonist; keratinocyte; medical schools; melanocyte; melanoma; microphthalmia-associated transcription factor; migration; new therapeutic target; novel; skills; skin disorder; small molecule; transcription factor; tumor; unpublished works

DESCRIPTION (provided by applicant): I have spent the last ten years building an expertise in the study of cAMP microdomains, specifically those regulated by the novel protein soluble adenylyl cyclase (sAC). During my training in dermatology, I applied the techniques and skills I have developed to the understanding of hyper proliferative keratinocyte skin disease, which led to a recent publication in the Journal of Investigative Dermatology. Over the past year, I began to explore the role of cAMP signaling in melanoma. I have developed two fruitful collaborations with experts in melanoma biology, Dr. Wolchok and Dr. Bastian at Memorial Sloan Kettering Cancer Center (MSKCC), and have continued my collaboration with an expert in sAC biology, Dr. Buck. Dr. Bastian and Dr. Buck will serve as my mentors during my training, and Dr. Wolchok will serve as an advisor. Over the next five years, I will have the privilege of being trained at both a world-class cancer research institution, MSKCC, and a leading medical college, Weill Cornell Medical Center (WCMC), both located at one of the most prestigious research corners in the world (WCMC/MSKCC/Rockefeller), proximity to which allows for unprecedented resources and exposure. Over the next five years, I have formulated a plan to further my expertise in cAMP signaling and develop my knowledge in melanoma biology. My short- term plan is to continue my education in order to become a physician scientist in dermatology. My long-term goal, in five years, is to secure R01 funding as an independent investigator. Melanoma is the sixth most common human cancer and one of the deadliest. Once melanoma spreads beyond the skin, effective medical interventions are limited. While certain signaling pathways, such as the Ras/Raf/ERK pathway, have well- established roles in controlling melanoma pathogenesis, recent clinical trials and basic science reports suggest that blocking this pathway alone is an insufficient treatment for melanoma. It has become apparent that the development of an effective treatment for melanoma relies on an improved understanding of the intricacies of melanoma signaling. cAMP has been implicated in a variety of signaling pathways that are key to the development and pathogenesis of melanoma, but in many cases the source and ramifications of cAMP signaling is poorly understood. A new class of adenylyl cyclases called soluble adenylyl cyclase (sAC) was recently characterized, and I was involved in developing a cadre of novel small molecule and genetic inhibitors capable of differentiating sAC-generated and the canonical G-protein sensitive transmembrane adenylyl cyclase (tmAC)-generated cAMP. In the past, I have used these reagents to establish the role of sAC in nerve growth factor-induced Rap activation in PC-12 cells, netrin-induced growth cone chemotaxis in primary neurons, and glucose-induced cAMP in beta cells. In each of these cases, involvement of cAMP was known, but a suitable model to explain its role was lacking. By differentiating tmAC- from sAC-dependent cAMP, more coherent models have been developed. I have applied these techniques to melanoma biology and have found that sAC protein migrates into the nucleus in human melanocytic proliferations as melanocytes acquire cellular atypical. In the past, I demonstrated that nuclear sAC activates the cAMP responsive binding protein transcription factor. I have also discovered that sAC protein is upregulated in melanoma, and inhibitors of sAC block melanocyte growth. In this proposal I plan to evaluate the relative contributions of sAC and tmAC microdomains in melanoma pathogenesis. I predict that this line of investigation will lead to novel therapeutic targets of melanoma.

描述（由申请人提供）：我在过去的十年中一直在研究营地微域研究，特别是由新型蛋白质可溶性腺苷酸环化酶（SAC）调节的camp微区域。在皮肤病学培训期间，我应用了我开发的技术和技能，以理解超增殖性角质形成细胞疾病，这导致了《研究性皮肤病学杂志》的最新出版物。在过去的一年中，我开始探索营地信号在黑色素瘤中的作用。我已经与黑色素瘤生物学专家，沃尔乔克博士和巴斯蒂安博士在纪念Sloan Kettering癌症中心（MSKCC）开发了两项富有成果的合作，并继续与SAC生物学专家Buck博士继续合作。巴斯蒂安博士和巴克博士将在我的培训期间担任我的导师，沃尔乔克博士将担任顾问。在接下来的五年中，我将有幸在世界一流的癌症研究机构，MSKCC和一所领先的医学院Weill Cornell Medical Center（WCMC）中接受培训，它们都位于世界上最著名的研究角落之一（WCMC/MSKCC/Rockefeller），允许无限制的资源和经验丰富。在接下来的五年中，我制定了一项计划，以进一步提高营地信号的专业知识并发展我在黑色素瘤生物学方面的知识。我的短期计划是继续我的教育，以成为皮肤病学的医师科学家。我五年来我的长期目标是作为独立调查员获得R01的资金。黑色素瘤是第六个最常见的人类癌症，也是最致命的癌症之一。一旦黑色素瘤扩散到皮肤超出皮肤，有效的医疗干预措施就会受到限制。虽然某些信号通路（例如RAS/RAF/ERK途径）在控制黑色素瘤发病机理中具有良好的作用，但最近的临床试验和基础科学报告表明，仅阻止此途径是对黑色素瘤的足够治疗方法。显而易见的是，有效的黑色素瘤治疗方法取决于对黑色素瘤信号传导复杂性的改善。 CAMP与多种信号通路有关，这些信号通路是黑色素瘤发育和发病机理的关键，但是在许多情况下，cAMP信号传导的来源和后果知之甚少。最近对一类称为可溶性腺苷酸环化酶（SAC）的新型腺苷酸环化酶进行了表征，我参与了开发一个能够区分囊的小分子和遗传抑制剂的干部，并且能够区分囊肿的G-蛋白敏感敏感的跨膜敏感的跨膜adenyllyl环酶（TMAC）。过去，我使用这些试剂来确定SAC在PC-12细胞中的神经生长因子诱导的RAP激活中的作用，Netrin诱导的原发性神经元中的生长锥趋化性以及葡萄糖诱导的β细胞cAMP。在每种情况下，都知道营地的参与，但是缺乏解释其作用的合适模型。通过将TMAC-与SAC依赖性营地区分开来，已经开发了更多连贯的模型。我已经将这些技术应用于黑色素瘤生物学，发现SAC蛋白在黑素细胞增殖中迁移到核中，因为黑色素细胞获得了细胞非典型的非典型。过去，我证明了核囊会激活cAMP反应性结合蛋白转录因子。我还发现，SAC蛋白在黑色素瘤中被上调，SAC抑制剂构成黑色素细胞的生长。在此提案中，我计划评估SAC和TMAC微域在黑色素瘤发病机理中的相对贡献。我预测，这种研究系列将导致黑色素瘤的新型治疗靶标。